Cyclic-AMP (cAMP) response element binding protein (CREB) belongs to a large family of basic leucine zipper (bZIP)-containing transcription factors including c-Jun, c-Fos and c-Myc. The protein serves a variety of biological functions including cellular proliferation, differentiation and adaptive responses. These processes are mediated by selectively transcribing a subset of CREB target genes activated by phosphorylation of CREB at Ser133 by mitogen- or stress-activated protein kinases. The phosphorylated CREB (p-CREB) is then able to bind the mammalian transcription co-activator, CREB-binding protein (CBP), via the KID (kinase-inducible domain) domain in CREB and KIX (KID-interacting) domain in CBP. This binding event will further recruit other transcriptional machinery to initiate gene transcription. Recently, it was discovered that another family of transcription co-activators, transducers of regulated CREB (TORCs), cooperates with CBP to confer the selective activation of target genes in response to distinct cellular signals.
Recent studies have revealed that CREB is overexpressed in many different cancer cells and participates in the regulation of immortalization and transformation of normal cells. In human prostate cancer (PCa), immunohistochemical analysis of primary and bone metastatic prostate cancer tissue from patients demonstrated that normal or benign prostate glands showed no detectable p-CREB. On the other hand, positive p-CREB staining was detected in poorly-differentiated cancers and bone metastatic tissue specimens. The increased level of activated p-CREB was associated with increased transcription of a CREB target gene VEGF (vascular endothelial growth factor). This positive correlation between the level of p-CREB and the extent of tumor differentiation and metastasis suggests that CREB is involved in tumor progression and metastasis. Overexpression of CREB was also seen in cancer tissues from breast cancer patients, non-small-cell lung cancer (NSCLC) patients, and the blast cells from patients with acute myeloid leukemia (AML).